Adenovirus Vector-based Vaccine Approach for Emerging Influenza Viruses

Since 1996, there have been numerous reports of human infections with avian influenza A viruses of subtypes H5N1, H7N7 and H9N2. In 2013, a new avian influenza virus strain of H7N9 subtype emerged in China causing more than 1559 infections in humans resulting in 616 deaths so far. Although human-to-human transmission has been infrequent and limited, genetic reassortment between avian and human/porcine influenza viruses or mutations in some of the genes leading to virus replication in the upper respiratory tract in humans could result in the generation of a novel pandemic influenza virus strain that not only can infect but also effectively transmit among the human population which would have little or no immunity to the new virus. Various strategies to develop effective vaccines against H5, H7, and H9 viruses have been evaluated. In general, these strategies yielded low to no cross-reactivity immune responses against antigenically distinct heterologous viruses from other clades. Hence, newer vaccine approaches with the potential to induce both humoral and cellular immune responses are needed to confer protection against a broad range of influenza viruses and their clades and subclades emerging from avian reservoirs. The main aim of this project is to determine whether bovine adenovirus (Ad) [BAd] vector-based influenza vaccine approach will be better than that of the human Ad [HAd] vector-based strategy. The proposal is based on the hypothesis that intranasal immunization with BAd vector-based influenza vaccine may serve a better option due to the presence of sialic acid receptors (the primary receptors for BAd internalization) in the respiratory tract. The goals of this proposal are: i) Determination of bovine adenoviral vector-based H5N1 influenza vaccine immunogenicity and protection efficacy in a mouse model (Aim 1); ii) Determination of the decline of Ad vector immunity with time and its effect on repeat immunization with the same Ad vector (Aim 2); and iii) Potential approach to obtain consistency in titration of various adenoviral vectors (Aim 3). Since the nature of the next pandemic influenza virus is unknown, Dr. Mittal’s laboratory overall efforts will be directed towards the generation of universal influenza vaccines that are broadly protective against H5, H7 and H9 influenza subtypes (as well as H1 and H3 subtypes) and thus could significantly lower morbidity, hinder transmission and prevent mortality in a pandemic situation before a strain-matched vaccine can be produced